The present invention relates to a medicament for the prevention or treatment of a disease accompanied with an increase in eosinophils, a pharmaceutical composition for the prevention or treatment of allergic diseases, and a medicament for suppressing an increase in eosinophils.
Eosinophils are granulocytes comprising 1 to 3% of peripheral blood leukocytes and are believed to be involved in allergic dermatitis or bronchial asthma and other allergic diseases or parasitic infections and other conditions (Eur. Respir. J. Suppl. 22, 109s, 1996). A disease condition where the ratio of eosinophils in the peripheral blood increases to 6% or more is called xe2x80x9ceosinophiliaxe2x80x9d. This condition is also observed in various skin disease (e.g., herpes, cnidosis, psoriasis, eczema), hematological diseases (e.g., myelocytic leukemia, pernicious anemia), infectious diseases, (e.g., cholera, malaria), and, bone diseases (e.g., sarcoma, rickets, myelitis), etc. in addition to the above diseases.
Eosinophils have granules containing basic cytotoxic proteins called MBP (major basic proteins), ECP (eosinophil cationic proteins), EDN (eosinophil-derived neurotoxins), etc. (Pharmacol. Rev. 51, 213, 1999). When allergic reactions or inflammation reactions occur, it is believed that eosinophils migrate to and infiltrate into these inflammatory areas, then cause degranulation and release these cytotoxic proteins so as to exacerbate these reactions (Trends Pharmacol. Sci. 16, 418, 1995). The major cytokines involved in the proliferation and differentiation of eosinophils are IL-5 (Interleukin-5), IL-3 (Interleukin-3), GM-CSF, etc. Further, RANTES or eotaxins and other chemokines play an important role in the accumulation of eosinophils in inflamed sites (Int. Arch. Allerg. Immunol. 113, 196, 1997, J. Leukoc. Biol. 59, 1, 1996).
It has been reported that various substances such as steroids (Br. J. Pharmacol. 101, 821, 1990), phosphodiesterase inhibitors (J. Pharmacol. Exp. Ther. 278, 1356, 1996), cyclosporins (Pharmacol. Rev. 51, 213, 1999), and tacrolimus (Br. J. Pharmacol. 120, 130, 1997) inhibit the functions of eosinophils, but they are not sufficiently satisfactory in terms of efficacy, specificity, side effects, etc. In addition, several anti-allergic agents are known to suppress the functions of eosinophils (Pharmacol. Rev. 51, 213, 1999), but the main mechanisms of their action is an antagonist action against histamine acceptors. It is unclear to what extent this action on eosinophils is involved in the clinical effects of these medicaments. That is, the relationship between the proliferation or function of eosinophils and the diseases including eosinophilia, allergic diseases and inflammation has not yet been elucidated.
On the other hand, chymase is a serine protease stored in mast cell granules, and widely present in tissues such as the skin, heart, vascular walls, intestines, etc. (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.; New York, 1995). Recently, it has been reported that administration of human chymase induce infiltration of leukocytes including cosinophils in mice as well as guinea pigs (Br. J. Pharmacol. 125, 1491, 1998). Further, it has been reported that human chymase acts on the precursor of IL-1xcex2 (Interleukin 1xcex2) and converts it to active type IL-1xcex2 (J. Exp. Med. 174, 821, 1991), which is known to induce eosinophil inflation by augmentation of expression of cell adhesion molecules (Am. J. Respir. Cell. Mo. Biol. 13, 555, 1995, J. Invest. Dermatol. 100, 417, 1993). Moreover, chymase cleaves membrane-bound stem cell factor (SCF) to form soluble SCF (Proc. Natl. Acad. Sci. U.S.A. 94, 9017, 1997). Further, recently, it has been reported that SCF is involved in the accumulation of eosinophils (J. Immunol. 156, 3945, 1996). These findings suggest that chymase is related to the role of eosinophils. At the present time, a search is going on for substances which can inhibit the activity of chymase in vivo with the aim of clarifying the role of chymase in the body and the possibility of chymase inhibitors as pharmaceuticals.
There are chymase inhibitors such as low molecular weight chymase inhibitors such as shown in textbooks (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), xcex1-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), xcex1,xcex1-difluoro-xcex2-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent--Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc. have been reported, but no satisfactory medicament or treatment method using inhibition of the activity of chymase as a strategy for treatment has yet been established.
The object of the present invention is to provide safe medicament for the prevention or treatment of diseases accompanied with an increase in eosinophils, which suppresses the progress of the condition, prevents progress of complications, and improves the quality of life of the patient.
The present inventors engaged in intensive studies to attain the above object and, as a result, found that a chymase inhibitor specifically reduces the number of eosinophils in the peripheral blood, elucidated the relationship between chymase activity and the increase in number of eosinophils, whereby the present invention is completed.
In accordance with the present invention, there is provided a medicament for the prevention or treatment of diseases involving an increase of eosinophils having a chymase inhibitor as its effective ingredient.
In accordance with the present invention, there is also provided a pharmaceutical composition for the prevention or treatment of allergic diseases containing an amount of a chymase inhibitor suppressing an increase in the eosinophils and a pharmaceutically acceptable vehicle.
In accordance with the present invention, there is further provided a medicament for the suppression of an increase in eosinophils having a chymase inhibitor as its effective ingredient.
In this specification, the diseases involving an increase in eosinophils include diseases whose onset is caused by an increase of eosinophils, diseases whose conditions are aggravated by an increase in eosinophils, and diseases whose cure is delayed by an increase in eosinophils. These diseases include, for example, allergic diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, cnidosis, and eczema.
The chymase inhibitor able to be used in the present invention can be selected as a substance inhibiting chymase activity by the use of methods workable by persons skilled in the art. As the method of selection, for example, the method of Example 1 explained below may be used. The compounds obtained in this way include known compounds previously reported as chymase inhibitors, for example, the low molecular weight chymase inhibitors such as shown in textbooks (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), xcex1-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), xcex1,xcex1-difluoro-xcex2-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese Unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc., but as a representative example of a preferable chymase inhibitor, a compound of the following formula (I) and its pharmaceutically acceptable salts may be mentioned. 
wherein, the ring A represents an aryl group;
R1 represents a hydroxyl group, an amino group, a C1 to C4 lower alkylamino group which may be substituted with a carboxylic acid group, a C7 to C10 lower aralkylamino group which may be substituted with a carboxylic acid group, an amino group acylated with a C1 to C4 lower aliphatic acid which may be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a C1 to C4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group, a C1 to C4 lower alkyl group substituted with a carboxylic acid group, or a C2 to C4 lower alkylene group which may be substituted with a carboxylic acid group;
R2 and R3 may be the same or different and represent a hydrogen atom, an unsubstituted or substituted C1 to C4 lower alkyl group, a halogen atom, a hydroxyl group, a C1 to C4 lower alkoxyl group, an amino group, an unsubstituted or substituted C1 to C4 lower alkylamino group, an unsubstituted or substituted C7 to C10 aralkylamino group, an amino group acylated with a C1 to C4 lower aliphatic acid which may be substituted with a carboxylic acid group, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a C1 to C4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group, or a carboxylic acid group or
when the ring A is a benzene ring, R1 and R2 may form, together with the substituting benzene ring, a fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group and R3 is the same as defined above; and
X represents a hydrogen atom, a C1 to C4 lower alkyl group, a C1 to C4 lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, or a nitro group.
In the general formula (I), preferable examples of the aryl group represented by the ring A are a benzene ring and a naphthalene ring.
Preferable examples of the C1 to C4 lower alkylamino group which may be substituted with the carboxylic acid group and the C7 to C12 lower aralkylamino group which may be substituted with a carboxylic acid group represented by R1 are a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a carboxymethylamino group, a carboxyethylamino group, a carboxypropylamino group, a carboxybutylamino group, a benzylamino group, a phenetylamino group, a phenylpropylamino group, a phenylbutylamino group, a carboxybenzylamino group, a carboxyphenetylamino group, a carboxyphenylpropylamino group, a carboxyphenylbutylamino group, etc.
Preferable examples of the amino group acylated with a C1 to C4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R1 are a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, a carboxypyrrolecarbonylamino group, etc.
Preferable examples of the amino group sulfonylated with a C1 to C4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R1 are a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a butanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybutanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, a carboxypyrrolesulfonylamino group, etc.
Preferable examples of the C1 to C4 lower alkyl group substituted with a carboxylic acid group represented by R1 are an acetic acid group, a propionic acid group, a butyric acid group, a valeric acid group, etc.
Preferable examples of the C2 to C4 lower alkylene group substituted with a carboxylic acid group represented by R1 are an acrylic acid group, a crotonic acid group, etc.
Preferable examples of the unsubstituted or substituted C1 to C4 lower alkyl group represented by R2 or R3 are a straight-chain alkyl group such as a methyl group, an ethyl group, a n-propyl group, and a n-butyl group and a branched alkyl group such as an isopropyl group, a sec-butyl group, and a t-butyl group.
Preferable examples of the substituent group of the C1 to C4 lower alkyl group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C1 to C4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group, a carboxyethylamino group, etc.
Preferable examples of the halogen atom represented by R2 or R3 are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Preferable examples of the C1 to C4 lower alkoxyl group represented by R2 or R3 are a straight-chain alkyloxy group such as a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group and a branched alkyloxy group such as an isopropyloxy group, a sec-butoxy group, and a t-butoxy group.
Preferable examples of the unsubstituted or substituted C1 to C4 lower alkylamino group represented by R2 or R3 are a methylamino group, an ethylamino group, a propylamino group, a butylamino group, etc.
Preferable examples of the substituent group of the C1 to C4 lower alkylamino group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C1 to C4 lower alkoxyl group, etc.
Preferable examples of the unsubstituted or substituted C7 to C12 lower aralkylamino group represented by R2 or R3 are a benzylamino group, a phenylethylamino group, a phenylpropylamino group, a phenylbutylamino group, etc.
Preferable examples of the substituent group of the aralkylamino group are a carboxylic acid group, a halogen atom such as a fluorine atom and a chlorine atom, a C1 to C4 lower alkoxyl group, etc.
Preferable examples of the amino group acylated with a C1 to C4 lower aliphatic acid which may be substituted with a carboxylic acid group, the amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid group, and the amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid group represented by R2 or R3 are a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a benzoylamino group, a naphthoylamino group, a pyridinecarbonylamino group, a pyrrolecarbonylamino group, a carboxyacetylamino group, a carboxypropionylamino group, a carboxybutyrylamino group, a carboxybenzoylamino group, a carboxynaphthoylamino group, a carboxypyridinecarbonylamino group, a carboxypyrrolecarbonylamino group, etc.
Preferable examples of the amino group sulfonylated with a C1 to C4 lower alkanesulfonic acid which may be substituted with a carboxylic acid group, the amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid group, and the amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid group represented by R2 or R3 are a methanesulfonylamino group, an ethanesulfonylamino group, a propanesulfonylamino group, a benzenesulfonylamino group, a naphthalenesulfonylamino group, a pyridinesulfonylamino group, a pyrrolesulfonylamino group, a carboxymethanesulfonylamino group, a carboxyethanesulfonylamino group, a carboxypropanesulfonylamino group, a carboxybenzenesulfonylamino group, a carboxynaphthalenesulfonylamino group, a carboxypyridinesulfonylamino group, a carboxypyrrolesulfonylamino group, etc.
Preferable examples of the fused heterocyclic ring which may be substituted with a carboxylic acid and in which the carbon atom in the ring may form a carbonyl group which R1 and R2 form together with the substituting benzene ring when the ring A is a benzene ring, are a tetrahydroquinoline ring and a benzoxazine ring, for example, a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline, a carboxybenzodioxane, etc.
Preferable examples of the C1 to C4 lower alkyl group represented by X are a straight-chain alkyl group such as a methyl group, an ethyl group, a n-propyl group, and a n-butyl group and a branched alkyl group such as an isopropyl group, a sec-butyl group, and a t-butyl group.
Preferable examples of the C1 to C4 lower alkoxyl group represented by X are a straight-chain alkyloxy group such as a methoxy group, an ethoxy group, a n-propyloxy group, and a n-butoxy group and a branched alkyloxy group such as an isopropyloxy group, a sec-butoxy group, and a t-butoxy group.
Preferable examples of the halogen atom represented by X, are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Further, examples of a pharmaceutically acceptable salts are an acid salt such as a hydrochloric acid salt, a methanesulfonic acid salt, and a trifluoroacetic acid salt and an alkali metal salt such as a sodium salt and a potassium salt.
The quinazoline derivative having the formula (I) according to the present invention may, for example, be synthesized by the following Synthesis Method (A) or (B).
Synthesis Method (A)
A compound having the formula (I-1): 
wherein the ring A is the same as defined above and R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 represent R1, R2 and R3, which may be protected with a protecting group, respectively, and R1, R2 and R3 represent the same as defined above
is reacted with an anthranilic acid derivative having the formula (I-2): 
wherein Xxe2x80x2 represents X, which may be protected with a protecting group, and X represents the same as defined above
using the method described, for example, in JP-A-6-199839 to obtain a sulfonylurea derivative having the formula (I-3): 
wherein the ring A, R1xe2x80x2, R2, R3xe2x80x2 and Xxe2x80x2 represent the same as defined above,
then, a condensing agent for example, 1,1xe2x80x2-carbonyldiimidazole (hereinafter referred to as CDI) is used to obtain the quinazoline ring, and if necessary, the protecting groups of R1, R2, R3 and X are deprotected.
In this reaction, when R1, R2 or R3 represents a group containing a hydroxyl group, an amino group, or a carboxylic acid group, R1, R2 or R3 may be optionally protected by a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. When X represents a hydroxyl group or an amino group, X may be optionally protected with a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc.
The compound having the formula (I-1) used in this reaction includes a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, using the synthesis method described in the specification of European Patent No. 0269141, it is possible to use a compound which can be synthesized from the corresponding sulfonamide derivative using chlorosulfonyl isocyanate. For example, it is possible to use 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate, 4-allyloxycarbonylmethylbenzenesulfonyl isocyanate, 4-allyloxybenzenesulfonyl isocyanate, etc.
As the anthranilic acid derivative having the formula (I-2) used for this reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, anthranilic acid, 4-chloroanthranilic acid, 4-methoxyanthranilic acid, 5-chloroanthranilic acid, 4-hydroxyanthranilic acid, etc. may be used.
The reaction to obtain the quinazoline ring from the sulfonylurea derivative having the formula (I-3) may be carried out using an aprotonic solvent such as, for example, an ether solvent such as tetrahydrofuran and dioxane, a halogen-containing solvent such as methylene chloride, or dimethylformamide etc. at a temperature of xe2x88x9250xc2x0 C. to 50xc2x0 C., preferably xe2x88x9220xc2x0 C. to room temperature. Further, for the cyclization reaction, it is possible to use an ordinary condensing agent which includes, for example, CDI, dicyclohexylcarbodiimide (DCC), and similar carbodiimide compounds, mixed anhydrides, etc. The deprotecting reaction can be carried out by an ordinary method using hydrolysis with an acid or alkali, reduction or oxidation etc.
Synthesis Method (B)
A compound having the formula (I-4): 
wherein the ring A, R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 represent the same as defined above
is condensed with an anthranilic acid derivative having the formula (I-5): 
wherein Xxe2x80x2 represents the same as defined above, Ph represents a phenyl group, and R4 represents a protecting group of the carboxyl group, which is specifically a group capable of being released by hydrolysis or hydrogenolysis, such as, for example, a methyl group, an ethyl group, or a benzyl group
using, for example, 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as DBU) to form a sulfonylurea derivative having the formula (I-6): 
wherein the ring A, R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4 and Xxe2x80x2 are the same as defined above,
which is then hydrolyzed with an alkali or hydrogenolyzed to derive a corresponding carboxylic acid represented by the formula (I-3), then the quinazoline ring is obtained and optionally the protecting groups of R1, R2, R3 and X are deprotected, in the same way as in Synthesis Method (A). In this reaction, when R1, R2 or R3 represents a group containing a hydroxyl group, an amino group, or a carboxylic acid group, R1, R2 or R3 may be optionally protected by a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc. When X represents a hydroxyl group or an amino group, X may be optionally protected with a protecting group such as a benzyloxycarbonyl group, a t-butoxycarbonyl group, a benzyl group, an allyl group, a t-butyl group, etc.
As the compound having the formula (I-4) used in the reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, 3-hydroxybenzenesulfonamide, 2-aminobenzenesulfonamide, 3-aminobenzenesulfonamide, 4-aminobenzenesulfonamide, (xc2x1)-2-(4-aminosulfonylphenyl)butyric acid, 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide, 4-benzyloxycarbonylamino-3-chlorobenzenesulfonamide, 4-amino-3,5-dichlorobenzenesulfonamide, 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide, 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide, 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide, 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide, 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide, 3-acetamide-4-methoxybenzenesulfonamide, 3-(3-aminosulfonyl)phenylacrylic acid t-butylester, 3-amino-4-methoxybenzenesulfonamide, 4-methoxy-3-methylsulfonylaminobenzenesulfonamide, 3-carboxy-4-hydroxy-2-naphthalenesulfonamide, 4-benzyloxycarbonylamino-3-t-butoxycarbonylbenzenesulfonamide, (xc2x1)-3-t-butoxycarbonyl-2-oxo-1H,3H-quinoline-7-sulfonamide, (xc2x1)-2-t-butoxycarbonyl-3-oxo-1,4-benzoxazine-6-sulfonamide, etc. may be used.
As the anthranilic acid derivative having the formula (I-5) used in this reaction, a commercially available or known compound or a compound which can be synthesized by a known method may be used. For example, methyl 4-chloro-2-N-phenoxycarbonylanthranilate, ethyl 4-chloro-2-N-phenoxycarbonylanthranilate, benzyl 4-chloro-2-N-phenoxycarbonylanthranilate, methyl 5-chloro-2-N-phenoxycarbonylanthranilate, ethyl 5-chloro-2-N-phenoxycarbonylanthranilate, benzyl 5-chloro-2-N-phenoxycarbonylanthranilate, methyl 4-methoxy-2-N-phenoxycarbonylanthranilate, ethyl 4-methoxy-2-N-phenoxycarbonylanthranilate, benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate, methyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, ethyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, benzyl 4-hydroxy-2-N-phenoxycarbonylanthranilate, etc. may be used.
The reaction for obtaining the compound having the formula (I-4) and the anthranilic acid derivative having the formula (I-5) condense to obtain a sulfonylurea derivative having the formula (I-6), may be carried out using an aprotic solvent, for example, an ether solvent such as tetrahydrofuran or dioxane, a halogen-containing solvent such as methylene chloride, or dimethylformamide etc. at a temperature of xe2x88x9250xc2x0 C. to 50xc2x0 C. preferably xe2x88x9220xc2x0 C. to room temperature. Further, as the usable for the condensation reaction, an organic strong base such as DBU, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide, or metal bases such as sodium hydride may be used.
In the reaction for alkali hydrolysis or hydrogenolysis of the sulfonylurea derivative having the formula (1-6) thus obtained to obtain the sulfonylurea derivative having the formula (I-3), ordinary hydrolysis conditions or hydrogenolysis conditions for esters may be used.
Note that the above reaction may be carried out while protecting the functional groups not involved in the reaction. According to the type of the protecting group, the protection is removed by chemical reduction or other ordinary protection-removing reactions. For example, when the protecting group is a t-butyl group or t-butoxycarbonyl group, trifluoroacetic acid may be used, while when it is an allyl group, palladium catalysts such as tetrakis(triphenylphosphine)palladium (0) may be used.
The compound having the formula (I), wherein R1 represents an amino group acylated with a C1 to C4 lower aliphatic acid which may be substituted with a carboxylic acid, an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a carboxylic acid and an amino group acylated with an heteroaromatic ring carboxylic acid which may be substituted with a carboxylic acid, can be obtained from the compound having the formula (I), wherein R1 represents an amino group, by acylating the same with carboxylic acid, carboxylic acid chloride, carboxylic acid anhydride using an ordinary method.
The compound having the formula (I), wherein R1 represents an amino group sulfonylated with a C1 to C4 lower alkane sulfonic acid which may be substituted with a carboxylic acid, an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a carboxylic acid and an amino group sulfonylated with an heteroaromatic ring sulfonic acid which may be substituted with a carboxylic acid, can be obtained from the compound having the formula (I), wherein R1 represents an amino group, by sulfonylating the same with sulfonic acid or sulfonic acid chloride using an ordinary method.
The product obtained according to the above-mentioned processes can be purified by a method such as recrystallization or column chromatography.
If necessary, the compounds having the formula (I) of the present invention obtained according to the above-mentioned processes can each be reacted with one of various acids or basis to convert the compound into their salt. Exemplary acids usable for the conversion of the compound having the formula (I) into their salts can include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, lactic acid, maleic acid, fumaric acid, tartaric acid, acetic acid, adipic acid, palmitic acid and tannic acid. Exemplary usable basis for the conversion of the compound having the formula (I) into their salts can include sodium hydroxide, lithium hydroxide and potassium hydroxide.
Further, the compounds having the formula (I) according to the present invention include those containing asymmetric centers. Each racemic mixture can be isolated by one or more of various methods, whereby a single optically-active substance can be obtained. Usable methods include, for example:
(1) Isolation by optically active column.
(2) Isolation by recrystallization subsequent to conversion into a salt with an optically active acid or base.
(3) Isolation by a combination of the above methods (1) and (2).
Evaluation of a medicament for the prevention or treatment for the disease related to eosinophil increase (e.g., bronchial asthma, allergic rhinitis, allergic conjunctivitis, cnidosis, eczema) can be performed by using peripheral eosinophilia models in addition to use of various disease models. For example, it is known that the number of peripheral eosinophils dramatically increases in the patients with asthma (in particular, chronic asthma) (Br. Med. J. 285 (6350), 1229, 1982), but administration of a steroid effective against bronchial asthma reduces the number of eosinophils in the peripheral blood (Eur. Respir. J. Suppl. 430s, 1989). It has been known for a long time that parasites such as Nippostrongylus brasiliensis cause an increase in eosinophils in animals. (Proc. Natl. Acad. Sci. USA 85, 4460, 1988). There has actually been a report that a steroid effective against bronchial asthma suppresses the increase in eosinophils induced by Nippostrongylus brasiliensis (Lab. Invest. 64, 224, 1991). Thus, parasite-induced eosinophilia model is thought to be useful for evaluation of a medicament for the prevention or treatment for asthma in which eosinophils play an important role. Such a parasite-induced model can also be used for evaluating amendicament for the prevention or treatment for other diseases in which eosinophils are involved e.g., allergic rhinitis, allergic conjunctivitis, cnidosis, and eczema.
The compound of the present invention can be evaluated by the suppressing effect on increase in eosinophils using the method described in Example 2, which is parasite-induced eosinophilia model.
To use the effective ingredient of the present invention as a pharmaceutical composition for the prevention or treatment of eosinophilia, various allergic diseases, and other diseases in which eosinophilis are involved, one or more of the compounds of the present invention may be mixed and formed into a form suitable for use in the method of administration by an ordinary method. Examples of preparation forms for oral administration include capsules, tablets, granules, fine granules, syrups, dry syrups, and other preparations, while examples of preparation forms for non-oral administration include injections and besides suppositories such as rectal suppositories and vaginal suppositories, transnasal preparations such as sprays and ointments, and percutaneous preparations such as tapes for percutaneous absorption.
The clinical dose of the compound according to the present invention varies according to the diseased condition, degree of seriousness, age, presence of complications, etc. and also varies according to its preparation form. In the case of oral administration, however, it may be dosed usually, in terms of effective ingredients, as 1 to 1000 mg per adult per day. In the case of non-oral administration, it is sufficient to administer {fraction (1/10)} to xc2xd the amount of the case of oral administration. These dosages can be suitably adjusted according to the age, the diseased condition, and the like of the patient to be dosed.
In the present invention, the chymase inhibitor can be administered alone as it is without being mixed with another effective ingredient, but considering the disease in question, the symptoms, complications, etc., it may also administered as a medicinal preparation containing other effective ingredients. Further, it may also be combined with these other effective ingredients. The amounts of the other effective ingredients used are not particularly limited, but are determined considering the minimum amounts for expression of their effects alone, the occurrence of side effects, etc.
In treatment, the form of preparation and the method of combined treatment including preparations containing the chymase inhibitor alone as an effective ingredient and preparations also containing other effective ingredients are suitably selected by a physician in accordance with the age of the patient, the symptoms, etc.
The toxicity of the compound according to the present invention is low. The acute toxicity values LD50 at 24 hours after oral administration to 5-week old male mice were 1 g/kg or more. This value is 50 or more times of the expected clinical amount of use and therefore these compounds are considered to be highly safe.